7-amino-2-methyl-3H-isoindol-1-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-dichloro-4-iodopyridine (0.2 g, 0.73 mmol), 7-amino-2-methyl-3H-isoindol-1-one (0.118 g, 0.73 mmol), palladium(II) acetate (6.56 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.025 g, 0.04 mmol) and cesium carbonate (0.476 g, 1.46 mmol) were suspended in dioxane (5 mL). The mixture was heated at 100° C. for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. A solid recovered from the top of the column was washed with water, dried in vacuo, and combined with the evaporated residue to afford 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3H-isoindol-1-one (0.160 g, 71% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.07 (3H, s), 4.50 (2H, s), 7.25-7.28 (1H, m), 7.48 (1H, s), 7.56-7.63 (2H, m), 8.36 (1H, s), 9.80 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=308.01 and 309.97 and 311.99. to cool to room temperature the product eluted first with MeOH Fractions containing product evaporated A solid recovered from the top of the column was washed with water dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure for Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 124A, 67.0 mg, 0.119 mmol) and 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Preparation XXXVIII, 26.9 mg, 0.166 mmol). The crude product was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which afforded the title material as an off-white solid, 54.8 mg (64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 8.37 (br s, 1H), 7.49 (br d, J=7.1 Hz, 1H), 7.37 (br t, J=7.1 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.60-4.74 (m, 4H), 4.45 (s, 2H), 3.74 (s, 3H), 3.61 (d, J=22.2 Hz, 2H), 3.06 (s, 3H). MS (ES+): m/z 688.08 (100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min). purified eluting with 0-5% MeOH concentrated in vacuo The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NBS (2.3 g, 12.96) was added to a cold (−8° C. to −10° C.) solution of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (2 g, 12.4 mmol) in DCM (40 mL) and the mixture stirred at −8° C. to −10° C. for 1 h. A solution of 10% aq. sodium thiosulfate (30 mL) was then added to the reaction mixture and stirring was continued for another 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water (3×40 mL) and brine (30 mL), and the organic layer was dried (Na2SO4) and concentrated in vacuo to yield 3.2 g of crude product. This material was triturated with ethyl acetate (10 mL) to give 2.2 g of pure 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXIX, yield: 74%). stirring was continued for another 20 minutes The layers were separated the aqueous layer was extracted with DCM (2×20 mL) The combined organic extracts were washed with water (3×40 mL) and brine (30 mL) the organic layer was dried (Na2SO4) concentrated in vacuo to yield 3.2 g of crude product This material was triturated with ethyl acetate (10 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXVIII, yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz). The reaction mixture was filtered the filtrate dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXVIII, yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz). The reaction mixture was filtered the filtrate dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., a solution of 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (232.6 mg, 1.43 mmol) in DMF (2.0 mL) is treated with 60% NaH (89.8 mg), stirred at the same temperature for 1.5 h, treated with a solution of 2,4,5-trichloropyrimidine (0.557 g) in DMF (3.5 mL), stirred for 1 h, and warmed to room temperature. After furthermore stirring for 13 h, the mixture is treated with sat. aqueous NH4Cl (6 mL), and the resulting brown precipitates are collected by a filtration, followed by washing with H2O, hexane, and CH3CN to give 7-(4-Amino-2,5-dichloropyrimidin-4-yl)amino-N-methyl-2,3-dihydroisoindole-1-one (130.2 g, 0.416 mmol) in 26%. Brown solid. Rf (CH2Cl2/EtOAc 1:1) 0.50. 1H-NMR (400 MHz, CDCl3): 3.22 (s), 4.43 (s), 7.15 (d, J=8.0), 7.59 (dd, J=8.0, 8.0), 8.24 (s), 8.71 (d, J=8.0), 11.05 (br. s). stirred for 1 h After furthermore stirring for 13 h the resulting brown precipitates are collected by a filtration by washing with H2O, hexane, and CH3CN

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At room temperature, a solution of N-Methyl-7-nitro-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated with SnCl2.2H2O (2.68 g), stirred at 80° C. under reflux for 5 h, and treated with 30 mL of 5N NaOH at 0° C. After the both layers are separated, the aqueous layer is extracted with EtOAc (2×8 mL), the combined extracts are washed with brine (5 mL), dried (MgSO4), and evaporated to give 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (455.9 g, 2.81 mmol) in 96%. Yellow solid. Rf (CH2Cl2/EtOAC 1:1) 0.53. 1H-NMR (400 MHz, CDCl3) 3.12 (s), 4.28 (s), 5.20 (br. s), 6.56 (d, J=8.0), 6.68 (d, J=8.0), 7.21 (dd, J=8.0, 8.0). under reflux for 5 h After the both layers are separated the aqueous layer is extracted with EtOAc (2×8 mL) the combined extracts are washed with brine (5 mL) dried (MgSO4) evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 17F, 6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz). The reaction mixture was filtered the filtrate dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NBS (2.3 g, 12.96) was added to a cold (−8° C. to −10° C.) solution of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 17E, 2 g, 12.4 mmol) in DCM (40 mL) and the mixture stirred at −8° C. to −10° C. for 1 h. A solution of 10% aq. sodium thiosulfate (30 mL) was then added to the reaction mixture and stirring was continued for another 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water (3×40 mL) and brine (30 mL), and the organic layer was dried (Na2SO4) and concentrated in vacuo to yield 3.2 g of crude product. This material was triturated with ethyl acetate (10 mL) to give 2.2 g of pure 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (yield: 74%). 1H NMR (CDCl3 400 MHz): δ 3.14 (s, 3H), 4.20 (s, 2H), 5.20 (bs, 2H), 5.49 (d, 1H, J=8.4 Hz), 5.79 (d, 1H, J=8.4 Hz). stirring was continued for another 20 minutes The layers were separated the aqueous layer was extracted with DCM (2×20 mL) The combined organic extracts were washed with water (3×40 mL) and brine (30 mL) the organic layer was dried (Na2SO4) concentrated in vacuo to yield 3.2 g of crude product This material was triturated with ethyl acetate (10 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure for Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 124A, 67.0 mg, 0.119 mmol) and 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Preparation XXXVIII, 26.9 mg, 0.166 mmol). The crude product was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which afforded the title material as an off-white solid, 54.8 mg (64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 8.37 (br s, 1H), 7.49 (br d, J=7.1 Hz, 1H), 7.37 (br t, J=7.1 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.60-4.74 (m, 4H), 4.45 (s, 2H), 3.74 (s, 3H), 3.61 (d, J=22.2 Hz, 2H), 3.06 (s, 3H). MS (ES+): m/z 688.08 (100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min). purified eluting with 0-5% MeOH concentrated in vacuo The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which